Biomedical subjects

Mikael C I Karlsson

Publications and source records attributed to Mikael C I Karlsson.

3 recordsLinked to original sources

PubMed2026

DNA methylation landscape of cerebrospinal fluid cells in multiple sclerosis: an epigenome-wide association study.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system in which DNA methylation may link genetic and environmental risk factors. METHODS: We profiled genome-wide DNA methylation in cerebrospinal fluid (CSF) cells from people with MS (pwMS) and matched controls. Differentially methylated positions (DMPs) and regions (DMRs) were integrated with transcriptomic data, T-cell chromatin annotations, and pathway analyses. Protocadherin gamma (PCDHγ) expression was assessed in primary CD4+ T-cell subsets and confirmed by flow cytometry. FINDINGS: We identified 2710 DMPs and 4330 DMRs associating with genes that were enriched in immune signalling, adhesion and migration processes, and were accompanied by corresponding RNA changes. MS-associated methylation changes enriched in the cohesin chromatin-regulation pathway localised to T-cell regulatory regions, and this pathway included multiple protocadherin (PCDH) genes, which displayed consistent methylation and expression changes in CSF cells of pwMS compared to controls. PCDHγ cluster gene expression was detected in CD4+ T-cell subsets, and flow cytometry confirmed PCDHγ protein expression in peripheral blood T cells. Moreover, co-expression analysis suggests a role of PCDH genes in aryl hydrocarbon receptor (AHR) signalling. Protein-level validation showed fewer PCDHγ-positive CD4+ T cells in pwMS and activation-induced PCDHγ upregulation after T-cell stimulation. INTERPRETATION: DNA methylation changes in CSF resident cells reflect dysregulated T cell activation and migration in pwMS and suggest involvement of protocadherin molecules in MS pathogenesis. FUNDING: European Research Council, Swedish Research Council, Swedish Brain Foundation, Swedish MS Foundation, Knut and Alice Wallenberg Foundation, European Union and others.

Humans↗

PubMed2003

Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone.

The marginal zone of the spleen is a precisely ordered region that contains specialized subsets of B lymphocytes and macrophages. Disruption of the negative signaling inositol phosphatase, SH2-containing inositol-5-phosphatase 1 (SHIP), results in the loss of marginal zone B cells (MZBs) with reorganization of marginal zone macrophages (MZMOs) to the red pulp of the spleen. This primary macrophage defect, as revealed by selectively depleting SHIP in myeloid cells shows that MZMOs are specifically required for the retention of MZBs. The MZMO phenotype was reverted in SHIP/Bruton's tyrosine kinase (Btk) double knockout mice, thus identifying the Btk activating pathway as an essential component being regulated by SHIP. Furthermore, we identified a direct interaction between the MARCO scavenger receptor on MZMOs and MZBs. Activation or disruption of this interaction results in MZB migration to the follicle. The migration of the MZMOs was further studied after the response to Staphylococcus aureus, which induced MZMOs to move into the red pulp while MZBs migrated into the follicular zone. The marginal zone is therefore a dynamic structure in which retention and trafficking of B cells requires specific macrophage-B cell interactions.

Animals↗

PubMed2002

Disruption of cell-cell adhesion enhances antibody-dependent cellular cytotoxicity: implications for antibody-based therapeutics of cancer.

Resistance to antibody-based anticancer approaches has become of considerable interest because of the rapidly growing clinical use of several different monoclonal antibodies as therapeutic agents, coupled with the recent finding that their efficacy may be attributable in part to their participation in host antibody-dependent cellular cytotoxicity. In this proof-of-concept study, we demonstrate the novel ability of an antiadhesive antibody (SHE78-7), targeted at the potent homophilic cell adhesion molecule E-cadherin, to play a dual role as participant in, and sensitizing agent for, host immune-mediated antitumor activity. SHE78-7 disrupted preformed multicellular aggregates (spheroids) of HT29 colon carcinoma cells both in vitro and in vivo in an ascites tumor xenograft model, but had no direct antitumor effect in vitro. In vivo, however, i.p. injection of SHE78-7 significantly prolonged the survival of nude mice carrying established i.p. HT29 xenografts, most notably when injections were given biweekly. This antitumor effect was dependent on the antiadhesive effect of SHE78-7 and could be effectively recapitulated via treatment with a combination of nondisruptive anti-hMHC-I antibodies, capable of recruiting an F(c)-mediated immune response but ineffective as a monotherapy and antiadhesive F(ab')(2) fragments of SHE78-7. Furthermore, additional therapy experiments using such F(ab')(2) fragments, or mice lacking activating F(c)gammaRIII receptors or inhibitory F(c)gammaRIIB, unequivocally indicated a role for host antibody-dependent cellular cytotoxicity, mediated by F(c)gammaRIII and negatively regulated by F(c)gammaRIIB. Taken together, the results suggest a possible means of improving antibody-based therapies of cancer, namely targeting antigens, selectively expressed or up-regulated by target cancer cells, which mediate cell-cell adhesive functions.

Animals↗